Abstract
Platelet-derived growth factors (PDGFs) and their cognate receptors (PDGFRα/β) play critical roles in breast cancer progression and metastasis. This review summarizes current evidence of PDGF ligand and receptor expression patterns, oncogenic functions, prognostic significance and therapeutic targetability, with a specific focus on small molecule inhibition. PDGF-PDGFR signaling is known to contribute to epithelial to mesenchymal transition, cancer stem cell maintenance, desmoplasia, angiogenesis, and immune modulation. Additionally, the four PDGF ligands have distinct oncogenic functions. PDGFA and PDGFB have been implicated in breast cancer associated brain metastasis, while PDGFC has been shown to play a crucial role in fibroblast activation. PDGFD, while less studied, may activate epithelial to mesenchymal transition in breast cancer. High expression of PDGFA, PDGFB, PDGFC, and stromal PDGFRβ correlate with poor patient survival, highlighting their potential as candidate biomarkers. We specifically focus on evaluating current therapeutic strategies which target the PDGF-PDGFR axis, including neutralizing antibodies, aptamers, and small molecule inhibitors, which show preclinical promise but limited clinical success in breast cancer to date. We discuss future research directions with emphasis on identifying selective inhibitors, utilizing PDGF-PDGFR signaling components for patient stratification, and combination with immunotherapies.
Keywords: Breast cancer, PDGF, PDGFR, Prognosis, Small molecule inhibition, Therapeutics
1. Introduction
1.1. Breast cancer heterogeneity and continuing clinical challenges
Breast cancer is the most commonly diagnosed cancer throughout the globe, with around 2.3 million new cases (11.6% of all new cases) in 2022 alone [1]. Within the United States, the American Cancer Society predicts that in 2026, there will be 321,910 new cases, and 42,670 cases will result in patient death [2].
One of the primary reasons driving the high mortality rate in breast cancer is the enormous genomic and pathologic diversity of the disease [3,4]. Clinically, breast cancers are classified into subtypes according to the presence/absence of three receptors: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [5,6]. These receptors also serve as surrogate biomarkers for the luminal A (ER+/PR+/HER2−), luminal B (ER+/PR+/HER2+), HER2-enriched (ER−/PR−/HER2+), and basal-like (ER−/PR−/HER2−) molecular subtypes, which are well known to correlate with patient outcomes [7–12]. Patients with ER/PR+ disease exhibit the most favorable outcomes due to a high response to anti-hormone therapies [13]. Over the years, patients with HER2+ disease have had increasingly more favorable outcomes due to novel and effective anti-HER2 targeting agents such as antibody-drug conjugates [14]. In contrast, patients with tumors lacking ER, PR, and HER2, called triple negative breast cancer (TNBC), tend to have the least favorable outcomes due to historically limited treatment options [15]. However, more recent clinical studies have revealed that outcomes can be improved with poly(ADP-ribose) polymerase (PARP) inhibitors, cyclin-dependent kinase (CDK) inhibitors, and immune therapies [16,17].
Along with directing patient prognosis, the receptor/molecular subtype also influences where breast cancer is likely to metastasize, including distant vital organs. For example, patients with metastatic ER−/PR+ /HER2− disease develop metastases in their bones at higher rates (51%) than in other organs (liver, 19%; lung, 17%, central nervous system, 9%), while HER2+ and TN tumors metastasize to multiple organs without any apparent organ preference [18]. Analogous numbers have been observed in multiple studies [19–22]. Importantly, metastatic site is associated with a patient’s overall survival, where patients with metastasis in the central nervous system (CNS), lung, liver, and bone confer median overall survival rates of 10–11, 30, 31, and 41 months, respectively [23,24]. Given that breast cancer mortality is almost entirely due to metastatic progression, the development of new therapeutic strategies focusing on metastasis is key to bettering patient outcomes, and in our view, it is the metastatic context where PDGF-PDGFR inhibition is most likely to have clinical impact due to its known roles in tumor-stromal signaling.
We review here the substantial evidence that has been presented over the last decade supporting platelet-derived growth factor receptor (PDGFR) signaling as a critical pro-tumorigenic/pro-metastatic signaling node in breast cancer. While other reviews have focused on PDGF signaling across malignancies or on specific biological contexts, a comprehensive assessment of breast cancer subtype-specific biology, prognostic utility, and clinical trial outcomes in breast cancer has been lacking. Here, we aim to identify the most effective contexts of targeting PDGF/PDGFR signaling and provide a framework for future patient therapeutic strategies. Search criteria for our assessment are summarized in Table 1.
Table 1.
Overview of search criteria, separated by section. Pre-clinical searches (Pubmed) excluding reviews, clinical trials, and machine-learning based studies.
| Section | Database | Key Words | Date Completed |
|---|---|---|---|
| Prognostic Utility | Pubmed | ((prognostic) OR (survival)) AND (pdgf) AND (breast cancer) AND (patient) | 10/2025 |
| PDGF Neutralizing Antibodies | Pubmed | (pdgf) AND (neutralizing antibody) AND (breast cancer) | 10/2025 |
| PDGFR Neutralizing Antibodies | Pubmed | (pdgfr) AND (neutralizing antibody) AND (breast cancer) | 10/2025 |
| Aptamers | Pubmed | ((pdgf) OR (pdgfr)) AND (aptamer) AND (breast cancer) | 10/2025 |
| Imatinib | Pubmed | *reviewed landmark studies and studies within last 5 years | 10/2025 |
| ClinicalTrials.gov | (imatinib) AND (breast cancer) | 12/2025 | |
| Pazopanib | Pubmed | (pazopanib) AND (breast cancer) | 11/2025 |
| ClinicalTrials.gov | 12/2025 | ||
| Sunitinib | Pubmed | (sunitinib) AND (breast cancer) | 11/2025 |
| ClinicalTrials.gov | 12/2025 | ||
| Sorafenib | Pubmed | (sorafenib) AND (breast cancer) *reviewed through page 10 | 11/2025 |
| ClinicalTrials.gov | (sorafenib) AND (breast cancer) | 12/2025 | |
| Nilotinib | Pubmed | (nilotinib) AND (breast cancer) | 11/2025 |
| ClinicalTrials.gov | 12/2025 | ||
| Crenolanib | Pubmed | (crenolanib) AND (breast cancer) | 11/2025 |
| ClinicalTrials.gov | 12/2025 | ||
| CP-673,451 | Pubmed | (CP–673,451) AND (breast cancer) | 11/2025 |
| ClinicalTrials.gov | 12/2025 |
1.2. Tumor-stromal PDGF-PDGFR signaling in breast cancer
PDGF-PDGFR signaling has long been acknowledged to have pathological significance in breast cancer and other solid tumors [25–29]. We have recently reviewed its role in breast cancer [30] and refer the reader to this book chapter as well as other recent reviews that cover other malignancies [31–34]. That said, we will briefly overview PDGF/PDGFR expression localization and oncogenic function to set the stage for our discussion of this signaling pathway’s clinical utility.
1.2.1. PDGF ligand expression and oncogenic function
The PDGF ligand family is comprised of PDGFA, PDGFB, PDGFC, and PDGFD. These monomeric polypeptides homo/heterodimerize to form five distinct dimers: PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. These dimers activate PDGFRα and PDGFRβ depending on lineage/tissue-specific expression patterns, where high PDGF-AA and PDGF-CC preferentially activate PDGFRα, and high PDGF-BB and PDGF-DD preferentially activate PDGFRβ [35–37]. Although these five polypeptide dimers belong to a single protein family, each plays a distinct role in normal physiology. Their contributions to breast cancer progression are equally nuanced and will be briefly explored below.
Expression of PDGFA and PDGFB has long been acknowledged in breast cancer, where expression is observed in the cancerous epithelium [25–29]. PDGFA is highly expressed in the majority of human tissues, with the highest level of expression observed in the heart, pancreas, and skeletal muscle [38]. The temporal expression of PDGFA has been extensively studied in murine models, where both PDGFA and PDGFB are highly expressed during embryonic development, with PDGFA specifically expressed in epithelial cells [39]. In breast cancer, PDGFA is a transcriptional target of forkhead box protein M1 (FoxM1), where transcriptional activation of PDGFA by FoxM1 in turn activates the AKT signaling pathway, leading to increased cell proliferation, as well as tumorigenesis in vitro [40]. Along with PDGFB, PDGFA has been shown to play a major role in breast cancer-associated brain metastasis via upregulation due to loss of miRNA let–7d and gain of hypoxia-inducible factor 1 (HIF1) [41,42]. In vitro studies using MCF–7 cells expressing a dominant-negative PDGFA mutant have highlighted its significant role in breast tumor desmoplasia, a process that contributes to tumor growth and metastatic spread through extracellular matrix (ECM) remodeling. [43,44]. Although PDGFA plays significant roles in breast cancer progression and metastasis, the majority of research has historically focused on other PDGF family members.
In addition to expression in the cancerous breast epithelium [25–29], PDGFB is highly expressed in endothelial cells [45], where its normal function in vascular stability and angiogenesis can be hijacked by tumor cells [46]. Specifically, when cancer cells, including lung, ovarian, renal cell carcinoma, and glioblastoma, express high levels of PDGFB, they recruit PDGFRβ + pericytes away from the endothelial surface, resulting in leaky vasculature and increased metastasis [47]. Although the mechanism for how PDGFB mediates breast cancer progression is still unclear, our group and others have confirmed a pro-tumorigenic/pro-metastatic role through direct interaction with stromal PDGFRβ [41, 42, 48–51]. High levels of secreted PDGFB have also been shown to initiate in vivo migration of adipose-derived stem cells via PDGFRβ activation, which activates proangiogenic signaling [52,53]. Lymphangiogenesis has also been shown to become activated via PDGFB-PDGFRβ signaling, which in turn may result in increased breast cancer tumor progression and metastasis [54]. These observations suggest that the oncogenic effect of PDGFB occurs due to interactions with multiple cell types within the TME, which generally lead to angiogenesis and vascular changes. It is important to note that PDGFB expression has also been reported on other tumor-associated populations, including macrophages and fibroblasts, which further complicates how the PDGFB-PDGFRβ signaling pathway function in cancer progression [55–58].
Expression of PDGFC has been observed in epithelial cells, neuronal progenitors, and musculature, as well as cancer cells [59]. The expression of PDGFC in breast cancer varies by subtype, with the highest levels observed in basal B cancers, relatively high levels in basal A cancers, and low levels in luminal breast cancers [60]. Tumor-derived PDGFC has been observed to induce migration of fibroblasts via paracrine signaling, where PDGFC-activated fibroblasts potentiate breast cancer cell invasion, indicating an oncogenic role of tumor-stomal PDGFC signaling in breast cancer [61]. More recent studies have confirmed PDGFC’s activation of cancer-associated fibroblasts (CAFs), specifically finding that PDGFC deficiency decreased fibrotic and angiogenic responses within the breast tumor microenvironment (TME) in a murine model [62]. These findings highlight an important role for PDGFC in stromal remodeling. Activated CAFs contribute to ECM deposition, matrix composition, and establishment of a fibrotic TME. Given that CAFs are a major player in the TME, PDGFC-mediated activation may have global effects in the breast cancer setting. Furthermore, the secretion of PDGFC by malignant tumor cells has been shown to affect the survival of tumor-associated macrophages (TAMs) by inhibiting caspase action through PDGFRα [63]. Notably, TAMs isolated from PDGFC deficient tumors exhibited increased apoptosis, indicating a role for PDGFC in maintaining pro-tumorigenic macrophages in the TME. Together, it is clear that the function of PDGFC in breast cancer is complex, but further research on PDGFC, specifically in immune modulation, is of great interest.
PDGFD is the most recently discovered member of the PDGF family, and it acts exclusively on PDGFRβ receptors expressed by tumor cells or cells within the TME [36]. The role of PDGFD in breast cancer is not as well defined as other PDGFs. However, recent studies have provided insight into how PDGFD may affect breast cancer progression and metastasis. PDGFD is highly expressed in both human breast carcinomas and human breast cancer cell lines, but is only weakly to moderately expressed in epithelial and stromal cells of normal human mammary tissue [64]. Published studies have reported that PDGFD signaling may play a role in the proliferation, apoptosis, and metastasis of breast cancer cells. Specifically, silencing of PDGFD in MDA-MB–231 cells decreased proliferation and colony formation and increased the rate of apoptosis in cell culture [65]. In vivo mouse experiments have also shown growth inhibition of primary tumors and increased survival times in mice with PDGFD-silenced tumors, as well as increased growth and lymph node metastasis in mice with PDGFD overexpressing tumors [64,65]. Investigations have also uncovered evidence that PDGFD may play a role in the activation of epithelial-to-mesenchymal transition (EMT) in cancer cells. Specifically, these studies showed that the EMT of breast cancer cells in response to conditioned media from adipose-derived stem cells was inhibited by PDGFD-neutralizing antibodies, suggesting adipose-derived stem cell induction of EMT is PDGFD dependent [66]. Although PDGFD signaling in breast cancer is not entirely understood, this growth factor plays crucial roles in primary tumor growth and metastasis, and further investigation of its function is warranted.
1.2.2. PDGF receptor expression and oncogenic function
Expression of PDGFRα is limited to stromal fibroblasts in the normal mammary gland [67–69]. In breast cancer, total tumor PDGFRα expression has been reported in 39% of cases [70]. This expression patterning has been further broken down into stromal versus aberrant epithelial expression, where stromal-specific PDGFRα has been reported in 1% [71] and 12% [72] of cases, and epithelial-specific PDGFRα has been reported in 20% [73] and 27% [72] of cases. PDGFRβ is limited to the stroma in the normal mammary gland, with expression observed in fibroblasts, pericytes, and vascular smooth muscle cells [74]. This expression patterning is mirrored in breast cancer, where high PDGFRβ is often localized only to the stromal compartment [74]. That said, there are reports of high PDGFRβ in breast carcinoma epithelial cells and cancer cell lines [48,75,76]. In addition, stromal-specific PDGFRα and PDGFRβ have been investigated in breast cancer metastatic sites. In this analysis, high stromal PDGFRα was observed in 21.9% of bone and 9.6% of lung metastasis, and high stromal PDGFRβ was observed in 40.6% of bone, 10.5% of brain, 20% of liver, and 57.7% of lung metastasis [77]. As with any biomarker immunostaining analysis, all results are likely dependent on the antibody used and the clinical-pathological parameters of each cohort, but combined, support a complex combination of both epithelial and stromal contributions for PDGFR in breast cancer progression.
Considering a stromal-specific pro-tumorigenic function for PDGFR, in vivo knockout mouse studies have revealed PDGFRα signaling promotes connective tissue remodeling, an important process for tumor growth and progression [78]. In this mouse model, PDGFRα-deficient fibroblasts and macrophages were less active in remodeling ECM. These data are supported by work conducted by us where a transgenic mouse expressing mesenchymal-specific hyperactive PDGFRα (Fsp1-cre; Pdgfra+/D842V) was developed and observed to exhibit increased mammary gland fibrosis associated with increased collagen deposition [67]. Mammary tumor cells grow faster orthotopically in Fsp1-cre; Pdgfra+/D842V mice compared to controls, indicating a pro-tumorigenic role for PDGFRα mediated stromal remodeling. [67]. We have made a similar mesenchymal-specific hyperactive PDGFRβ (Fsp1-cre; Pdgfrb+/D849V) genetically engineered mouse model (GEMM) and have confirmed stromal PDGFRβ signaling increases breast cancer tumorigenesis and metastasis, specifically to the brain, via PDGFB (tumor) to PDGFRβ (stromal) paracrine signaling [42].
Wound healing and tissue repair via fibroblast activation is a key function for normal PDGF-PDGFR signaling that is often exploited by cancer cells during oncogenesis to produce CAFs. These CAFs can induce phenotypic changes in the ECM of tumor cells, leading to a variety of tumorigenic effects, including enhancing cell invasion and angiogenesis [79–82]. Research on CAFs in relation to PDGF-PDGFR signaling, as well as PDGF-PDGFR signaling in breast cancer in general, is complex and ongoing, specifically on immune cell regulation within the TME. However, PDGFRβ+ CAFs have been shown to regulate breast cancer proliferation and metastasis via integrin α11, which promotes CAF-induced breast cancer invasion [83]. Mechanistically, integrin α11 interacts with PDGFRβ in a PDGF-BB-dependent manner, enhancing downstream JNK signaling production of tenascin-C, a pro-invasive matricellular protein that promotes extracellular matrix remodeling and tumor cell invasion. Pharmacological inhibition of PDGFRβ or JNK significantly impaired CAF-driven breast cancer invasion in this study. However, the complete function of PDGFR signaling in breast CAFs still remains unknown and should be an area of future research.
Like stromal PDGFR signaling, high PDGFR in transformed breast epithelium is also pro-tumorigenic and multifaceted. Given that PDGFR is not normally expressed in this epithelial lineage, the presence in cancer is likely a result of EMT of the luminal mammary epithelial cells. This is evidenced in a study by Jechlinger and colleagues, where they show autocrine PDGFR signaling maintains transforming growth factor-β (TGF-β)-induced EMT in both mouse and human breast cancer cell line models [48]. Without PDGFR signaling, TGF-β induces apoptosis rather than EMT. Moreover, the activation of the EMT in breast cancer can be mediated by TGF-β signaling through the LIM-homeobox gene 2 (LHX2) transcription factor, which upregulates Pdgfb mRNA transcription and subsequent PDGFRβ paracrine activation [49]. These findings support substantial crosstalk between TGFβ and PDGF signaling axes, with PDGF signaling stabilizing TGFβ-mediated processes such as fibroblast activation and stromal remodeling. Upregulation of PDGFRβ has also been observed in insulin-like growth factor 1 receptor (IGF–1R)-resistant mammary tumor mouse models, where EMT was found to be the main resistance mechanism, as well as in Twist-overexpressing human mammary epithelial cells, one of the most highly studied EMT regulators [84–86]. As PDGFRβ and PDGFRα are both involved with EMT, their expression/function are consequently associated with cancer stem cells (CSCs) as well. The CSC subpopulation of certain human mammary epithelial cells has been shown to have a 40-fold increase in PDGFRA and 140-fold increase in PDGFRB mRNA expression, which in turn may cause a further shift from non-CSC to CSCs within solid tumors [85]. Lastly, autocrine PDGFRβ function in TNBC, the breast cancer subset with the highest CSC and EMT features, has been connected to the upregulation of key TNBC players, including CUB domain-containing protein–1 (CDCP1) [75].
1.3. Subtype specific roles of PDGF-PDGFR signaling in breast cancer
The functional and clinical relevance of PDGF-PDGFR signaling in breast cancer is highly dependent on molecular subtype. Increasing evidence suggests that expression of PDGF ligands and receptors varies across subtypes and may contribute to subtype-specific disease progression and therapeutic limitations.
1.3.1. PDGFs and PDGFRs in ER+ breast cancers
ER+ breast cancers demonstrate a context-dependent role for PDGF signaling. PDGF activity is generally lower in luminal tumors [87]. Specifically, patient data sets have shown gene expression of PDGFC and PDGFRβ is low in luminal breast cancers compared to other subtypes [60,72]. Several other studies have demonstrated a correlation between expression of PDGFRs and ER negativity [71,72,88].
Despite the low expression of PDGF in luminal breast cancers, there are several interactions that highlight subtype-specific mechanisms. Upregulation of PDGFRα and PDGFA induced by environmental exposure to cadmium has been linked to increased breast cancer cell proliferation via an estrogen receptor-α (ERα) dependent mechanism [89]. In this study, the presence of cadmium increased PDGFA mRNA and phosphorylated PDGFRα in MCF–7 cells. The addition of an ER-agonist then returned these levels back to baseline, supporting the patient data that demonstrates low PDGF signaling in ER+ breast cancers [89]. Interestingly, a recent study by Turrell et al. indicates PDGFC as a potential target to limit metastatic relapse in ER+ breast cancer [68]. In a murine model of ER+ breast cancer, dormant disseminated cancer cells (DTCs) express low levels of PDGFC. However, PDGFC, but not other PDGF family members, was elevated in metastatic lung lesions, indicating a role for tumor-derived PDGFC in ER+ DTC survival and outgrowth [68].
Collectively, these studies suggest that PDGF signaling is generally low in ER+ breast cancerss, and these patients may not be the best candidates for PDGF-targeted therapies. However, the role of PDGFC specifically in ER+ metastasis warrants further exploration.
1.3.2. PDGFs and PDGFRs in HER2+ breast cancers
Although relatively few studies have directly evaluated PDGF signaling in HER2+ breast cancer, several observations suggest this pathway may contribute to aggressive disease progression. Expression of both PDGFRα and PDGFRβ has been associated with HER2 positivity in patient cohorts [70,71]. Additional evidence supports a role for PDGF signaling in HER2-associated brain metastasis. Our group has previously examined a cohort of primary breast tumor samples and discovered that high levels of PDGFB protein in primary tumors correlated with shorter survival in patients with either TNBC or HER2+ disease that developed brain metastasis [42]. Our subsequent analysis of the METABRIC dataset revealed a similar association in HER2+ tumors that trended toward significance specifically for brain metastasis, but not for recurrence to other metastatic sites. Furthermore, preclinical studies using HER2-expressing brain-seeking breast cancer models demonstrated that the multikinase inhibitor pazopanib reduced experimental brain metastatic burden [90]. Together, these findings suggest that PDGFB-PDGFRβ signaling may contribute to the brain metastatic propensity of a subset of HER2+ tumors, although larger HER2-specific studies are needed for confirmation. These observations further support the concept that high PDGFB primary tumor expression may help identify those HER2+ patients at risk for developing brain metastases, and that PDGFR-targeting agents may be most clinically relevant in metastatic settings particularly when there is functionally relevant stromal involvement.
1.3.3. PDGFs and PDGFRs in TN breast cancers
In TNBC, PDGF signaling appears to play a particularly prominent role. PDGFC expression is enriched in basal-like subtypes and is prognostic of worse outcome in TNBC patients [60,91]. Additionally, PDGFRα expression is associated with higher histological grade and TNBC subtype based on a cohort of over 600 patient samples [72]. These results are consistent with another patient cohort that linked co-expression of PDGFC and PDGFRα to more aggressive breast cancers, specifically the TNBC subtype [73].
Several studies have demonstrated that EMT and CSC markers are enriched in TNBC, contributing to their aggressive nature [92], and as discussed previously, PDGFRβ signaling has been linked to both aggressive features [48,85]. Additionally, activation of PDGFRβ by PDGF-BB increases expression of CDCP1, a key player in migration and proliferation of TNBC cells [75]. Knockdown of PDGFRβ in TNBC cells attenuated this expression [75]. Similar results were seen in another study, where PDGFB-PDGFRβ signaling promoted TNBC proliferation and expression of zinc finger E-box binding homeobox 1 (ZEB1), an inducer of EMT [93]. Furthermore, inhibition of PDGFRβ suppressed TNBC proliferation and invasion both in vivo and in vitro [76,91]. Together, these studies highlight a prominent role for PDGFRβ signaling in TNBC, and provides support for targeting this pathway in TNBC. Additionally, elevated levels of the PDGF family in TNBC suggest patients with this subtype of breast cancer may represent one of the most promising populations for PDGF-targeted therapies. It is expected that uncovering both non-cell autonomous and cell-autonomous functions for PDGF-PDGFR signaling will continue to provide evidence for the clinical value of this pathway in breast cancer, both as prognostic biomarkers and therapeutic targets. We will review both utilities in the next sections.
2. Prognostic utility of PDGFs and PDGFRs in breast cancer
Given the extensive evidence supporting pro-tumorigenic functions of the PDGFs and PDGFRs in the TME, it is important to understand how this is reflected in patient outcomes. Recent studies have reported that expression of both PDGF ligands and their receptors can serve as pathologic and prognostic indicators in breast cancer (Table 2). Here, we will review these patient datasets and discuss how PDGF/PDGFR family expression may be used as a prognostic tool.
Table 2.
Overview of studies reporting utility of PDGF/PDGFR family members in breast cancer patient prognosis.
| Survival | mRNA/protein (Ab) | Outcome (better/worse) | Reference # | |
|---|---|---|---|---|
| PDGF Signature | DSS | mRNA | worse (P = 0.002) | 87 |
| RFS | mRNA | worse (P = 2.23E–09) | 94 | |
| PDGFA | OS | mRNA | NS | 42 |
| OS | serum protein | worse (P = 0.002) | 94 | |
| PFS | serum protein | worse (P < 0.05) | 95, 96 | |
| BrMFS | mRNA | worse (P = 0.006) | 41 | |
| PDGFB | OS | mRNA | worse (P = 0.021) | 42 |
| OS | mRNA | NS | 96 | |
| DFS | mRNA | worse (P = 0.009) | 96 | |
| DMFS | mRNA | worse (P < 0.03) | 42, 96 | |
| DMFS | protein (Cell Signaling 3169) | NS | 42 | |
| BrMFS | protein (Cell Signaling 3169)/mRNA | worse (P < 0.03) | 41, 42 | |
| BoMFS | protein (Cell Signaling 3169)/mRNA | NS | 42 | |
| LuMFS | protein (Cell Signaling 3169)/mRNA | NS | 42 | |
| LiMFS | protein (Cell Signaling 3169)/mRNA | NS | 42 | |
| PDGFC | OS | mRNA | NS | 42 |
| OS | protein (Ventana 6B3) | worse (P = 0.002) | 62 | |
| DFS | protein (GeneTex) | worse (P < 0.05) | 100 | |
| DMFS | mRNA | worse (P = 0.024) | 91 | |
| DRFi | protein (Karolinska Institute) | worse at 5 yr (P = 0.04), NS overall | 73 | |
| RFS | mRNA | NS | 91 | |
| PDGFD | OS | mRNA | better (P < 0.001) | 42 |
| OS | mRNA | worse (P = 0.005) | 99 | |
| PDGFRα | DRFi | protein (Cell Signaling 3164) | NS (P = 0.69) tumor, (P = 0.36) stroma | 73 |
| MFS | mRNA | worse (P = 0.022) | 104 | |
| PDGFRβ | DRFi | protein (Cell Signaling 3169) | NS (P = 0.16) stroma | 73 |
| RFS | protein (Cell Signaling 3169) | worse (P = 0.019) | 71 | |
| BCSS | protein (Cell Signaling 3169) | worse (P = 0.019) | 71 |
Abbreviations: Antibody (Ab), brain metastasis specific survival (BrMFS), bone metastasis specific survival (BoMFS), Overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), recurrence-free survival (RFS), distant recurrence-free interval (DRFi), distant metastasis-free survival (DMFS), metastasis-free survival (MFS), breast cancer-specific survival (BCSS), lung metastasis specific survival (LuMFS), liver metastasis specific survival (LiMFS), non-significant (NS).
2.1. PDGF Signature
In order to delineate the prognostic ability of the PDGF-PDGFR signaling pathway as a whole, a study conducted in 2013 by Olivia Frings et al. generated a gene signature of 113 genes to represent PDGF signaling in breast cancer [87]. This signature was then applied to over 900 patients across 4 public breast cancer datasets from Sweden and the Netherlands. The analysis revealed that a high PDGF signature score was associated with high tumor grade, ER negativity, and HER2 positivity across each dataset in univariate analyses. More interestingly, these results remained significant across multi-variate survival analyses, including more classic prognostic signatures, Ki67 status, and other stroma-related gene expression scores (Finak and CSR). Additionally, patients with a high PDGF signature score had shorter disease-specific survival (DSS) and recurrence-free survival (RFS), indicating the prognostic significance of PDGF signaling. [87].
2.2. PDGFA
PDGFA was first investigated as a prognostic factor by Seymour and colleagues in 1994. In a univariate analysis of a cohort of 58 advanced breast cancer patient punch biopsies, PDGF-AA immunostaining significantly correlates with reduced survival, where patients with positive PDGF-AA staining had a median survival time of 4.9 months versus 11.9 months for those with negative staining [94]. However, PDGF-AA positivity was not correlated with any breast cancer subtype or predictive of treatment response. A more recent analysis of over 800 patients across four publicly available datasets revealed that increased expression of PDGFA mRNA in the primary tumor correlates with shorter brain metastasis-free survival (BrMFS) [41]. Additionally, several clinical studies have linked levels of serum PDGF-AA to progression-free survival (PFS). One study treated 67 patients with metastatic breast cancer (MBC) with a combination of taxane and zoldronic acid. This study determined that low baseline PDGF-AA was significantly associated with longer PFS following treatment [95]. Similarly, a Phase II trial using an antiangiogenic agent (TSU–68) showed that baseline serum levels of PDGF-AA were predictive of drug efficacy. In this trial, patients with high baseline PDGF-AA had significantly worse PFS after treatment compared to control, whereas patients with low baseline PDGF-AA had a PFS benefit of 5.7 months [96]. Together, these studies consistently indicate that elevated mRNA, protein, and/or serum levels of PDGFA in patients is prognostic of worse outcome, regardless of subtype and across cohorts of varying size (Table 2).
2.3. PDGFB
Our group has previously investigated multiple publicly available breast cancer datasets and observed that high primary tumor PDGFB mRNA is prognostic of reduced overall survival (OS) and distant metastasis-free survival (DMFS), irrespective of subtype [42]. Further, a dataset of ER + breast cancer patients with high PDGFB mRNA have decreased disease-free survival (DFS), DMFS, and OS [97]. Studies from our group have also demonstrated that PDGFB plays a role in breast cancer associated brain metastasis. In a cohort of patients with TN and HER2 + breast cancers, high expression of PDGFB protein at the primary site was correlated with decreased brain metastasis-free survival (BrMFS). However, there was no correlation at other metastatic sites (bone, liver, lung) [42]. This aligns with a study from Curzio Ruegg, where high expression of PDGFB mRNA correlates with decreased BrMFS [41]. Interestingly, a recent study of serum from 103 patients indicated that increased PDGF-BB in the serum is significantly correlated with decreased tumor-infiltrating lymphocytes (TILs) [98]. However, a majority of these studies utilize only univariate analysis, and results should be viewed from this perspective. Future prognostic analysis of PDGFB should account for established clinicopathological variables. However, if validated prospectively, primary tumor PDGFB could represent a novel candidate biomarker for identifying patients at high risk for developing brain metastasis-specific recurrence.
2.4. PDGFC
Similar to PDGFA and PDGFB, PDGFC protein expression generally indicates a worse prognosis (Table 2). PDGFC mRNA is specifically associated with decreased DMFS (N = 232) and RFS (N = 618) in TNBC [91] and OS across tumor types [99]. Importantly, protein expression of PDGFC has also been reported to be significantly associated with reduced OS (N = 890) and DFS (N = 81) in breast cancer patients [62, 100]. Of note, PDGFC protein and RNA expression are significantly associated with worse outcomes across multiple datasets, although all reported studies were univariate. Additionally, patients with tumors positive for PDGF-CC have increased risk of a breast cancer event within 5 years of their primary diagnosis [73]. High PDGFC is also linked with more aggressive breast cancer phenotypes and is predominantly observed in basal-like breast cancers, specifically hormone receptor (HR) negative tumors [60,62,73].
2.5. PDGFD
As mentioned previously, PDGFD is the most recently discovered PDGF ligand, and there is no clear correlation between PDGFD expression and breast cancer prognosis. Higher PDGFD signature expression is associated with decreased OS in TCGA-BRCA, but high PDGFD mRNA is associated with increased OS in the METABRIC cohort [42,99]. Importantly, the TCGA study utilized a PDGFD signature, which combined PDGFD expression with genes highly correlated with PDGFD, which may have skewed the reported results. TCGA datasets utilized RNA sequencing to quantify mRNA expression while METABRIC utilized older microarray-based profiling, which can affect gene expression detection [101–103]. Additionally, basal-like tumors account for a relatively higher proportion of samples in the TCGA data set, while METABRIC is enriched for luminal subtypes. These subtype distribution differences may also bias PDGFD prognostic outcomes and additional studies are required to determine if there are subtype-specific outcome differences.
2.6. PDGFRα
High expression of PDGFRα in tumor cells has been linked with aggressiveness, including the TNBC subtype and tumors with a high histopathological grade [72]. Additionally, a study of over 600 patients, revealed that PDGFRα is lowly expressed in luminal breast cancers and is correlated with ER negativity and PR negativity [72]. A 2005 study of 181 invasive ductal carcinomas showed a positive correlation between PDGFRα tumor expression and HER2 positivity, which is commonly associated with increased aggresiveness [70]. PDGFRα has also been linked to breast cancer metastasis. In patients with inflammatory breast cancer, PDGFRα activation signatures are prognostic of decreased metastasis-free survival (MFS). Patients with PDGFRα-activated tumors had a 52% 5-year MFS versus 72% in patients with non--PDGFRα-activated tumors (N = 121), which held in both univariate and multivariate analyses [104]. Further, a significant upregulation of PDGFRα expression in tumor cells was reported in patients with lymph node metastasis [73].
2.7. PDGFRβ
A study of 512 breast tumor biopsies by Janna Paulsson et al. revealed a strong correlation between stromal PDGFRβ expression and ER negativity, PR negativity, HER2 positivity, tumor proliferation, and high histological grade [71]. This study also identified that stromal PDGFRβ expression is associated with shorter MFS and breast cancer-specific survival. Another study (N = 989) confirmed that high stromal PDGFRβ is associated with ER negativity and significantly increased risk of recurrence [88]. Together, these analyses indicate a relationship between PDGFRβ expression and poor breast cancer prognosis (Table 2).
Several additional studies have supported PDGFRβ as a predictive marker for response to breast cancer treatment. Analysis of the SweBCG91RT trial (N = 989) determined that radiotherapy (RT) was less beneficial for patients with high stromal PDGFRβ compared to low in a multivariate analysis [88]. Further, another analysis by the same group revealed that a PDGFRβ score was predictive of RT benefit in the SweDCIS trial (N = 716). Patients with low expression of stromal PDGFRβ had decreased rates of ipsilateral breast events within 10 years, correlating to an absolute risk reduction of 21%, which was significant in both univariate and multivariate analysis [105]. Moreover, analysis of a cohort of ER+ patients treated with aromatase inhibitor (AI) showed that high stromal expression of PDGFRβ post-treatment is correlated with shorter time to treatment failure, and tumor expression of PDGFRβ was elevated at the point of relapse [106].
Collectively, based on the current findings discussed above, PDGF-PDGFR signaling appears to function in breast cancer prognosis where expression of both PDGFs and PDGFRs by breast cancer cells is generally correlated with decreased OS and MFS. Although prognostic associations have been reported for each PDGF ligand and receptor individually, current evidence suggests that the strongest and most reliable prognostic associations involve stromal PDGFRβ expression and markers of PDGF-PDGFR activity. Unlike the individual ligand expression studies, which may be influenced by cohort composition, detection methodologies, and cellular source, stromal PDGFRβ and PDGF-PDGFR signaling signatures have been associated with poor outcomes in multiple studies with multivariate analysis and are supported by pre-clinical work linking signaling to CAF activation, fibrosis, angiogenesis, and metastasis. However, further prospective studies incorporating multi-variate analysis and multiple cohorts should be completed prior to the clinical implementation of PDGF-PDGFR biomarkers. Therapies targeting PDGF-PDGFR signaling pathways still present a fascinating and critical direction in breast cancer research and hold promise as beneficial therapeutic approaches.
3. Therapeutic strategies targeting PDGF-PDGFR signaling
PDGF-PDGFR signaling is responsive to pharmacological inhibition in various ways (Fig. 1). In this section, we will overview how this pathway can be blocked extracellularly through neutralizing antibodies as well as intracellularly using DNA/RNA aptamers and small molecule inhibition. Although no PDGF/PDGFR-targeted therapeutic is yet approved for breast cancer, much can be learned from our included discussion of these agents in other cancers.
Fig. 1.
Overview of pharmacological inhibition of the PDGF-PDGFR signaling pathway, including non-PDGFR receptor tyrosine kinase targets of small molecule inhibitors. Created in BioRender. Reardon, J. (2026) https://BioRender.com/66j9qlp.
3.1. PDGF ligand neutralizing antibodies
Neutralizing antibodies are an extremely effective way to block PDGF ligand signaling, especially when occurring through tumor-stromal cross talk. PDGF neutralizing antibodies were first shown to be effective in 1985 to inhibit acute fibroblast transformation caused by the simian sarcoma virus [107]. Other studies have since shown anti-tumor effects of PDGF-BB neutralizing antibodies in other cancer types, such as glioma, meningioma, and leukemia [108–111]. Blocking PDGF-AA or PDGF-BB has also been reported to reduce TGF-β1-induced proliferation in an androgen-resistant prostate cancer cell line model [112].
While studies have been limited in breast cancer, those reported do suggest potential efficacy of using neutralizing PDGF antibodies to reduce tumorigenicity in this disease type. For example, Bing Yi et al. demonstrated that PDGF-BB plays an essential role in osteosclerotic bone metastasis in a mouse model of human breast cancer (MCF–7/Neu), and neutralizing antibodies for PDGF-BB inhibited this bone formation activity [113]. Likewise, treatment of MC3T3-E1 osteoclasts with conditioned media from human breast cancer cells (MDA-MB–231) showed a reorganization of actin fibers. Osteoclast phenotype remained normal when MDA-MB–231 cells were treated with PDGF neutralizing antibody [114]. Additionally, in a system where conditioned media from radiation-treated breast cancer cells (MCF–7, MDA-MB–231) induces the paracrine induction of cancer cell and endothelial cell invasion via the IL-6/STAT3 and PDGF-BB/PDGFR signaling pathways, neutralizing PDGF-BB antibodies are capable of reducing this pro-tumorigenic effect [115]. Furthermore, Snigdha Banerjee et al. showed that PDGF-BB is required for breast cancer cell-induced migration of aortic smooth muscle cells (AOSMCs) in vitro, where the migration of the AOSMCs was significantly reduced by neutralizing PDGF-BB antibodies [116]. There is also report of adipose-derived stem cells secreting PDGF-DD, where conditioned media from these cells promotes breast cancer cell EMT, mammosphere formation, anchorage-independent growth, stem cell number, and 4T1 tumor growth in vivo [66]. Importantly, a neutralizing antibody to PDGF-DD can significantly reduce the adipose-derived stem cell-induced tumorigenic effects [66]. Together, strongly supporting PDGF ligands as valid therapeutic targets.
To date, neutralizing antibodies towards the PDGF ligands have not reached the clinic. Pfizer developed a PDGF-BB neutralizing antibody named MOR8457, which effectively blocked binding to PDGF receptor through structural contortions [117]. However, to our knowledge, this antibody has not advanced beyond pre-clinical testing.
3.2. PDGFR neutralizing antibodies
3.2.1. Preclinical findings
Neutralizing antibodies are also effective at blocking the PDGF receptors in a highly specific manner, and thus, have been developed and tested for clinical efficacy. Early pre-clinical work revealed an anti-PDGFRβ antibody (APB5) in combination with an anti-vascular endothelial growth factor (VEGF) aptamer was more effective than either alone at inducing vessel regression in an ocular model of neovascularization [118]. Interestingly, within the cancer setting, adipose-derived stem cells are a predicted source of perivascular cells that allow for new blood vessel formation in the context of tumor growth [52]. In this study, Sebastian Gehmert et al. demonstrated that neutralizing antibodies to PDGFRβ reduced adipose-derived stem cell migration towards MDA-MB–231 and 4T1 breast cancer-derived conditioned media (CM). This same group has further reported that PDGF-BB promotes, and neutralization with PDGFRβ antibodies blocks adipose-derived stem cell induced migration towards 4T1 cells [119]. Additional neutralizing antibodies, 1B3 and IMC–2C5, have also been developed and were reported to be efficacious in reducing tumor volume in xenograft models of other solid tumor types, especially when combined with an anti-angiogenic agent [120,121]. Altogether, these early studies provide pre-clinical support for translation of PDGFR neutralizing antibodies to the clinic.
3.2.2. Clinical findings
For use in humans, both anti-PDGFRα and anti-PDGFRβ antibodies [122] have been developed, with olaratumab (IMC-3G3, Lartruvo™), a selective anti-PDGFRα monoclonal antibody, being the most studied to date. Olaratumab blocks PDGFRα with no inhibitory effects on PDGFRβ and received accelerated approval for combined use with doxorubicin in advanced soft tissue sarcoma after exhibiting an overall survival benefit (11.8 months) in a multi-site Phase II (N = 133) trial [123]. Unfortunately, the confirmatory Phase III trial did not show any significant difference in overall survival, leading to withdrawal of Lartruvo™ for non-investigational use [124,125]. Given the early success of olaratumab in soft tissue sarcoma, a number of clinical trials in other solid tumors [e.g., pediatric CNS, ovarian, prostate, lung and gastrointestinal stromal tumors (GISTs)] were completed with mostly non-significant results [126–130]. To date, the only report for olaratumab clinical use in breast cancer is a single case report testing doxorubicin with olaratumab in two women diagnosed with phyllodes tumors of the breast [131]. Phyllodes tumors are extremely rare mesenchymal breast tumors that are clinically managed similar to sarcoma cases. In this small case study, the cancer in these women did not respond to the combination of olaratumab plus doxorubicin and progressed rapidly early in treatment. Of note, the authors did not histologically or molecularly characterize either patient for PDGFR expression or activation, which may be why this treatment failed. Even still, it is of great clinical interest to continue considering an antibody-based approach for PDGFR-targeting. As an example, a recent study takes advantage of PDGFRβ localization in CAFs as a tool to enhance CD40 immunotherapy. In this study, they develop a PDGFRBxCD40 AffiMab where they can activate CD40, a tumor necrosis factor (TNF) receptor and immunotherapy target, in a PDGFRβ-dependent manner [132].
3.3. DNA and RNA aptamers
DNA or RNA aptamers are single-stranded, short sequences that bind with high affinity and selectivity for a specific target. They are otherwise known as “chemical antibodies” and exhibit advantages over traditional antibodies in that they are temperature stable, are cheaper to produce, and exhibit higher tumor penetration and longer tumor retention [133]. Green et al. were the first to produce DNA aptamers against PDGF ligands [134]. The aptamer that targets the PDGF-BB chain has been demonstrated to bind to PDGF-BB more selectively (Kd ≈ 10−10 M) in PDGF-BB homodimers and PDGF-AB heterodimers compared to PDGF-AA (Kd > 10−8 M) [134]. This PDGF-B aptamer was subsequently shown to enhance the anti-tumor efficacy of Taxol in a xenograft model of thyroid cancer [135]. Another PDGF-B aptamer, AX102, has been shown to reduce tumor vessel density [136] as well as enhance cyclophosphamide efficacy in Lewis lung carcinoma and B-cell carcinoma mouse models [137], and enhance bevacizumab (Avastin®) an anti-angiogenic, in orthotopic ovarian cancer tumors (HeyA8 and SKOV3ip1) [138].
An aptamer targeting PDGFRβ (Gint4.T) has been generated and tested in breast cancer models. One study revealed the anti-PDGFRβ aptamer can inhibit homing of bone marrow-derived mesenchymal stem cells (BM-MSCs), which highly express PDGFRβ, towards the MDA-MB–231 TNBC microenvironment [139]. Similarly, in the 4T1 murine model of TNBC, combination PDGFRβ aptamer plus an anti-PD-L1 mAb was effective at reducing tumor growth and metastasis to the lung, and this reduction corresponded with increased infiltration of T-cells [140]. Likewise, it was demonstrated that this PDGFRβ aptamer blocked invasive growth and migration of two mesenchymal human TNBC cancer cell lines (MDA-MB–231, BT–549) and decreased formation of lung metastases in the MDA-MB–231 model [76]. Thus, targeting either PDGF-BB or PDGFRβ using aptamers could be a valid therapeutic strategy in breast cancer. Certainly, as an option in the TNBC metastatic setting.
3.4. Small molecule inhibitors
Historically, small molecules have been the most widely used therapeutic strategy to inhibit PDGFR signaling. That said, the ATP binding pocket is highly conserved across tyrosine kinases with homology between PDGFR and others including VEGFR, c-KIT, RET, ABL, and FMS-like tyrosine kinase (FLT). Thus, as shown in Fig. 1, the development of highly selective PDGFR inhibition has been challenging [141]. Small molecule inhibitors targeting PDGFR can broadly be classified into two categories: (1) relatively-selective PDGFR inhibitors (crenolanib, CP–673,451) and (2) multi-targeted tyrosine kinase inhibitors (TKIs) that inhibit PDGFR alongside other kinases such as VEGFR, c-KIT, and ABL (imatinib, pazopanib, sunitinib, sorafenib, nilotinib). This distinction is critical, as lack of selectivity in multi-kinase inhibitors contributes to their complex biological effects and limited clinical efficacy. An additional challenge in interpreting preclinical studies is that many commonly used breast cancer cell lines express low or undetectable levels of PDGFRα/β levels unless they have undergone EMT. In our experience, the MDA-MB–231 cells are one of the few models we discuss here that exhibit detectable PDGFRβ expression. Thus, responses to PDGFR inhibition, especially when using multi-kinase inhibitors, should be interpreted with this limitation in mind, as these effects may reflect non-PDGFR signaling and may differ from non-cell autonomous tumor-stromal mechanisms observed in vivo. In the following sections, we will discuss preclinical and clinical findings relevant to breast cancer for these agents with consideration of their selectivity and implications of clinical use. While a substantial portion of the literature discussed is derived from preclinical studies, there has been increasing clinical investigation of PDGF-PDGFR-targeted therapies across multiple cancer types. In breast cancer specifically, numerous studies have evaluated PDGFR inhibitors as either monotherapy or in combination with standard treatments, although clinical benefit has been modest. Notably, most of these trials do not incorporate biomarker-driven patient selection, which likely contributes to the lack of efficacy observed in these studies. The clinical trials where breast cancer patients were included are listed in Table 3.
Table 3.
Overview of clinical trials using small molecule inhibitors targeting PDGFR in breast cancer patients. Clinical trials completed prior to NCT registration requirement or non-US based are not included.
3.4.1. Imatinib mesylate
The development of Imatinib mesylate (N-(4-methyl–3-{[4-(pyridin–3-yl)pyrimidin-2-yl]amino} phenyl)–4-[(4-methylpiperazin–1-yl)methyl]benzamide; also known as Glivec, Gleevec or STI571) marked a significant advancement in the treatment of chronic myeloid leukemia (CML) in 2001 [142]. Imatinib was discovered to target the Abl kinase [143] and for those patients harboring the BCR-Abl fusion “Philadelphia chromosome (Ph+)”, this drug was a game-changing therapeutic option. Importantly, although its primary target was found to be the Abl kinase, imatinib mesylate is a potent inhibitor of other protein tyrosine kinases, including PDGFRα, PDGFRβ and c-Kit [143] (Fig. 1), which has led to its use in other cancer types. Currently, imatinib has FDA approval in the pediatric setting for Ph + CML and acute lymphoblastic leukemia (ALL). For adults, it is approved for the treatment of Ph + CML, ALL, myelodysplastic/myeloproliferative diseases (with PDGFR gene rearrangements), aggressive systemic mastocytosis (ASM), hypereosinophilic syndrome (HES) and eosinophilic leukemia (CEL) (with FIP1L1-PDGFRA fusion or if fusion status is unknown), advanced dermatofibrosarcoma protuberans (DFSP), advanced GIST and in the adjuvant setting following GIST (Kit-CD117 +) resection [144]. Imatinib is not FDA approved for use in breast cancer but attempts to determine clinical efficacy have been completed as we will now discuss.
3.4.1.1. Preclinical findings.
Several preclinical studies have demonstrated that imatinib exhibits anti-tumorigenic effects on breast cancer cells. Early studies showed promising inhibition of tumor growth (IC50 = 5–6 μM) in the MCF–7 human epithelial breast cancer cell line and the highly invasive ZR–75–1 and MDA-MB–231 lines, with further evidence suggesting a cytostatic mechanism of action [145]. Although not directly studying PDGFRβ inhibition, Turrell et al., show that imatinib-directed inhibition of PDGFRα was able to significantly reduce lung colonization of PDGFC-mediated ER + tumors (TSAE1, HRM1, EMT6) [68]. Importantly, Weigel et al., show PDGFRB expression in MCF–7, ZR–75–1, MDA-MB–231, and T47-D cells [146]. Imatinib treatment significantly inhibited in vitro growth and PDGFRβ and AKT phosphorylation in all 4 cell lines. Additionally, imatinib induced apoptosis in all cell lines, which was amplified after co-treatment with vinorelbine, an anti-mitotic chemotherapeutic [146]. A third in vitro study revealed that following PDGF stimulation, imatinib had a potent inhibitory effect on breast cancer cell (MDA-MB–231, MCF–7) proliferation, invasion, migration, and cell surface expression of heparan sulfate proteoglycans [147], which play important roles in regulating the functional and mechanical properties of cancer cells [148,149]. Together, implying that this drug is effective at reducing PDGFR driven signaling, although effects on other tyrosine kinase activity werenot excluded.
In 2006, the first in vivo pre-clinical study evaluating imatinib in breast cancer was published, which revealed that imatinib could significantly reduce lung metastasis following tail-vein injection of EpRas cells [48]. Follow-up studies have confirmed the action of imatinib on PDGFRβ in vivo, including a report on imatinib reducing lung metastasis in a modified MMTV-PyMT model with increased PDGFB-PDGFRβ signaling induced by mammary-specific overexpression of LHX2 [49]. Additionally, systemic administration of imatinib mesylate significantly reduced tumor size and skeletal lesions through enhanced apoptosis of tumor and endothelial cells in a model of tibial metastasis (MDA-MB–435) [150]. However, it is impossible to separate the effect of blocking PDGFR on the cancer cells directly versus on the surrounding stroma. Indeed, inhibition of PDGFRs by imatinib or PDGFB aptamers reduces interstitial hypertension through direct effects on pericyte function and increases capillary-to-interstitial transport in an experimental rat colonic carcinoma [151]. As such, PDGFR + stroma can contribute to the hydrodynamic properties of tumor interstitium and could be a novel technique to increase drug uptake regardless of PDGFR positivity of the tumor epithelium itself [151,152].
3.4.1.2. Clinical findings.
Despite the promising anti-tumor activity in preclinical investigations, clinical trials with imatinib mesylate have been unsatisfactory in breast cancer, even when considering PDGFRβ tumor expression. Early work by Modi et al. illustrated that imatinib mesylate monotherapy in 16 severely pretreated MBC patients, at a dose of 800 mg/day, resulted in no evidence of significant clinical benefit [153]. This is due to an unexpectedly high incidence of toxicities, requiring 8 patients to have dose reductions and 4 patients to fully withdraw from the trial [153]. Furthermore, clinical investigation of Imatinib mesylate in PDGFRβ positive MBC showed no clinical activity and induced immunosuppressive effects, indicated by a significant reduction in T-cell infiltration after treatment (NCT00045188) [154]. Although the treatment was tolerated, all 13 patients experienced disease progression. Interestingly, recent in vitro studies of imatinib have also demonstrated a negative immunomodulatory effect that is primarily mediated via an effect on T-cell specific kinases [155–157].
Unfortunately, imatinib has shown limited efficacy as a combination therapy to date. Two Phase II trials tested imatinib in combination with docetaxel for the treatment of MBC (NCT00080665, NCT00193180). In both trials, the treatment was poorly tolerated and showed no benefit in response rate when compared to single-agent docetaxel [158,159]. Southwest Oncology Group Study 0338 showed that imatinib with capecitabine was well tolerated but did not improve response compared to capecitabine alone in 19 unselected MBC patients (NCT00087152) [160]. Only 8 tumor samples were acquired, all of which expressed PDGFRβ in the surrounding stroma, but showed no expression in the breast cancer cells [160]. Similarly, in 2018, Yam et al. performed a Phase II clinical study of combination therapy of imatinib mesylate and letrozole in 45 postmenopausal patients with HR+ and PDGFRβ or c-Kit positive MBC (NCT00338728). Although the combination therapy was well-tolerated, the HR+ MBC showed limited response [161]. The authors postulated that this ineffectiveness could be a result of increased ER signaling. Additionally, due to promising pre-clinical studies on the combination of imatinib and vinorelbine [146], the safety and efficacy of this combination have been tested in patients with advanced breast cancer, but as of the time of this review, results have yet to be released (NCT00372476). More recently, imatinib is being considered as a tool to convert TN breast cancer to ER+ in a Window-of-Opportunity trial, though recruitment is still currently underway (NCT05722795). Despite early pre-clinical successes, clinical evidence consistently has demonstrated that imatinib offers minimal therapeutic benefit and poor tolerability to patients with MBC, at least in the context that has been tested. That said, breast cancer is complex not only it its heterogeneity but in the many stages of disease progression. It is possible that imatinib has a role that has yet to be revealed.
3.4.2. Pazopanib
Pazopanib (5-[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino] pyrimidin-2-yl]amino-2-methylbenzenesulfonamide; Votrient™) is an orally administered TKI that targets protein tyrosine kinases, including VEGFR1-3, PDGFRα, PDGFRβ, and c-Kit [162,163] (Fig. 1). The US FDA has recently approved its use for the treatment of advanced renal cell carcinoma (RCC), and clinical testing is ongoing in a variety of other cancer types, including breast cancer [164–167].
3.4.2.1. Preclinical findings.
Pazopanib showed promise as a potent therapeutic in early pre-clinical work, with antiproliferative activity against the PDGFRβ+ brain seeking MDA-MB–231 cells with and without HER2 (231-BR, 231-BR-HER2) with an IC50 of 5 μM [90]. In the same study, 21 days of oral pazopanib administration (100 mg/kg) resulted in a 39% and 73% decrease in micro- and macro- brain metastases, respectively [90]. Pazopanib successfully inhibited MEK and ERK activation despite theMDA-MB–231’s constitutively active B-Raf and Ras mutations. Importantly, these findings imply that pazopanib can act directly on tumor cells and could prevent HER2+ breast cancer from advancing in the brain [90]. Moreover, Di Desidero et al. found that with combination therapy of pazopanib and topotecan, pazopanib significantly increased anti-tumor activity and prolonged longevity in an orthotopic model of the highly metastatic MDA-MB–231/LM2–4 cell line variant, with a significant decrease in tumor vascularity, proliferative index, and apoptotic induction [168]. These promising results have led to many clinical trials in breast cancer.
3.4.2.2. Clinical findings.
In an early Phase I trial of 60 patients (5 with breast cancer), pazopanib (800 mg dose) was generally well-tolerated, with three partial responses and prolonged stable disease in 14 of the patients (NCT00060151) [169]. Early combination studies suggested greater activity when pazopanib was paired with cytotoxic agents. Combination therapy of pazopanib with paclitaxel showed partial response in TNBC in a Phase I clinical trial, with an acceptable safety profile (NCT00388076) [170]. Similarly, the combination of paclitaxel and carboplatin with pazopanib showed partial response in MBC patients (NCT00388076) [171]. In addition, pazopanib with nonsteroidal aromatase inhibitors (NSAIs) resulted in a clinical benefit rate of 46.4% and 25% at week 12 and 24 respectively, in patients with NSAI-resistant advanced breast cancer (NCT01466972). Similarly, in a random Phase II study of 190 HER2+ MBC patients, a decrease in tumor progression and increase in response rate was observed in the lapatinib/pazopanib treated group compared to lapatinib monotherapy (36.2 and 22.2%, respectively) (NCT00347919) [172,173]. However, this combination was also associated with increased toxicity, and the improved response rate was not sufficient to warrant further development. Pazopanib with capecitabine in MBC showed a 25% increase in clinical benefit (NCT01498458). In other trials, pazopanib monotherapy or pazopanib with lapatinib showed no clinical benefit to MBC patients or inflammatory breast cancer patients respectively (NCT00509587, NCT00558103). A Phase I pazopanib and cisplatin combination therapy trial was also conducted, but neither drug could be administered at their single agent doses without significant toxicity and pharmacokinetic interactions (NCT01165385). Although pazopanib did not show significant clinical benefit as a monotherapy, it appears to add additional benefit in many combination therapy settings for MBC, but combination regimens clearly struggle to overcome toxicity issues. It is also possible that efficacy may be observed in the brain metastasis space as has been shown by us and other as just discussed, but these clinical trials likely excluded patients with CNS metastases from enrollment. This culture in clinical trials is changing and it is possible that pazopanib could again be considered as a way to prevent/treat CNS metastases.
3.4.3. Sunitinib malate
Sunitinib malate (N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide; Sutent®), an oral inhibitor of multiple receptor tyrosine kinases (RTKs), targets VEGFR1-3, PDGFR, c-Kit, and FMS-like tyrosine kinase-3 ligand (FLT3) [174–177] (Fig. 1). These RTKs have roles in breast cancer pathogenesis, microvascular support, and metastatic progression, and as such, this multi-kinase inhibitor is a compelling therapeutic strategy [71,178,179]. To date, Sutent® has been licensed for the treatment of advanced renal cell carcinoma (RCC), advanced metastatic pancreatic neuroendocrine tumor, and imatinib-resistant/intolerant GIST with progression or imatinib intolerance [180], and numerous clinical trials are testing its efficacy in breast cancer as discussed below. In fact, of all of the drugs discussed herein, sunitinib has the most trials completed to date.
3.4.3.1. Preclinical data.
Sunitinib administered alone, or in conjunction with other anti-cancer agents, has revealed anti-tumor effects in numerous breast cancer in vitro and xenograft models (MCF–7, MDA-MB–231, MDA-MB–468) [175,181]. Specifically, sunitinib inhibited proliferation and increased apoptosis of MCF–7 cells in vitro through inhibition of NF-κB expression [182]. Sunitinib alone was also found to inhibit osteolytic tumor progression in an experimental mouse model of breast cancer bone metastasis [177]. Several studies have also demonstrated sunitinib’s ability to decrease angiogenesis in breast cancer xenografts [175,183]. Further, Kodera et al. found sunitinib inhibited growth of MDA-MB–231 primary tumor and lymph node metastasis by blocking phosphorylation of VEGFR–2 and VEGFR–3 [184]. However, none of these studies provided data on PDGFR signaling.
Sunitinib has also been investigated in combination with conventional chemotherapy to reduce breast tumor growth. When combined with docetaxel, 5-fluorouracil, or doxorubicin, sunitinib reduced tumor growth and prolonged lifespan in both RAS-driven spontaneous mouse models and MDA-MB–435 xenografts [185]. In a HER2-amplified mouse model, a 75–80% larger decrease in tumor volume was observed following sunitinib plus trastuzumab treatment compared to single agents [183]. Similarly, combination treatment of sunitinib and IFN-γ increased the expression of apoptosis markers in vitro and significantly reduced in vivo tumor growth of a panel of HER2 + breast cancer cell lines [186].
Importantly, there have been several preclinical studies revealing sunitinib enhances metastasis in multiple organs, including brain, lung, and liver in xenograft mouse models of breast cancer (MDA-MB–231, 4T1) [187,188]. Mechanistically, this unintended result is perhaps not surprising given the known role for VEGFR and PDGFR in vascular viability/stability. Indeed, sunitinib was shown to increase breast cancer metastasis by inducing endothelial cell senescence, vessel leakiness and tumor cell extravasation into the blood stream [189]. In support, another study indicates that sunitinib treatment of TNBC tumors (MDA-MB–231, Hs578T) promotes invasion by enhancing vasculogenic mimicry (VM) and VM-associated proteins [190]. Sunitinib also been shown to have negative impacts on key players in the TME. Guti et al. demonstrated that sunitinib treatment diminishes activation of natural killer (NK) cells and inhibits cytotoxic effects of NK cells on the HER2+JIMT-1 breast cancer cell line [191]. Thus, the non-selective, multi-kinase nature of this drug does lead to a complex response that may or may not be anti-tumorigenic. Whether it is functions to block tumor growth andmetastases likely depends heavily on the tumor epithelial expression of PDGFB as discussed above, which was not evaluated in any of these studies.
3.4.3.2. Clinical data.
Due to sunitinib’s success in treating patients with RCC and GIST as well as preclinical findings in breast cancer, it was quickly investigated for potential use in breast cancer patients. Early Phase I studies determined that sunitinib was well tolerated as a neoadjuvant therapy (NCT00291577, NCT0065669, NCT00887575), and an additional Phase I study tested sunitinib in combination with docetaxel in patients with HER2+ MBC and showed partial response in 73% of participants (NCT00372424) [192]. These results led to numerous Phase II trials as monotherapy and in combination with other agents. In particular, a Phase II study of sunitinib monotherapy showed modest single-agent effects, with an 11% response rate in patients previously treated with anthracycline or taxane [193]. An additional Phase II trial testing intermittent low dose sunitinib in combination with doxorubicin or cyclophosphamide showed no improvement in pathological complete response rate, but did significantly increase vascular normalization index (NCT01176799) [194]. These findings suggest that while sunitinib effectively altered tumor vasculature, vascular remodeling did not translate into improved tumor control by itself. In a recent Phase II trial, addition of sunitinib to neoadjuvant chemotherapy showed a promising benefit for patients with ER+ locally advanced breast cancer, where response rate was higher compared to TN breast cancer (NCT00513695) [195]. This differential response may reflect greater dependence of ER+ tumors on stromal and growth factor signaling networks, however this is in contrast to pre-clinical data discussed in Section 1.3.3 that hypothesized greater dependency of TN breast cancer on PDGF signaling. It is important to note that many Phase II trials investigating sunitinib monotherapy or combination therapies were terminated early due to unacceptable risk to benefit ratio or toxicities (NCT00616122, NCT00824538, NCT00434356), and later expanded trials, specifically for intermittent low dose sunitinib, have not yet had results posted (NCT00662025, NCT01803503).
To date, four Phase III trials have been reported. The first compared sunitinib versus capecitabine monotherapy and showed no improvement of PFS in previously treated HER2-negative breast cancer patients (NCT00373113) [196]. In subsequent Phase III trials, sunitinib combination therapy regularly failed to increase survival in multidrug-resistant MBC when compared to other standard monotherapy and combination regimens (NCT00373256, NCT00393939, NCT00435409) [180, 196–198]. The lack of benefit despite strong pre-clinical rationale may reflect the heterogeneity of breast cancer and lack of biomarker-based patient selection for these trials. That said, sunitinib salvage treatment showed modest antitumor effect to Chinese patients with MBC, especially to those patients with carcinomatous ulcers [199]. Therefore, careful selection of patients may be necessary to observe benefit to sunitinib therapy in the metastatic setting.
3.4.4. Sorafenib
Sorafenib (4-[4-[[4-chloro-3-(trifluoromethyl)phenyl]carbamoylamino]phenoxy]-N-methylpyridine-2-carboxamide) is an oral antiproliferative and anti-angiogenic multi-kinase inhibitor that targets intracellular RAF kinase, VEGFR [1–3], PDGFR, RET, c-kit and FLT3 [200–203] (Fig. 1). Sorafenib is used clinically to treat advanced renal cell carcinoma and unresectable hepatocellular carcinoma [204,205] and is being evaluated for efficacy to treat patients with other solid tumors, including metastatic breast cancer [206–208].
3.4.4.1. Preclinical findings.
As sorafenib can inhibit intracellular RAF, early work focused on its use in treating solid tumors with oncogenic KRAS and BRAF mutations, including the MDA-MB–231 breast carcinoma cell line [200,209]. Sorafenib inhibits phosphorylation of VEGFR-2 in human endothelial cells and fibroblasts, as well as VEGFR-3 and PDGFR in human aortic smooth muscles cells [200] indicating direct effects on the TME and the complexity of how this drug acts systemically in patients
In preclinical cancer models, sorafenib inhibited proliferation, migration and invasion of breast cancer cells (MDA-MB–231, MCF–7) in vitro [210–213]. Additionally, oral sorafenib decreases tumor growth in human breast, colon, ovarian, thyroid, and pancreatic carcinomas, melanoma, RCC, hepatic cell carcinoma (HCC), and non-small cell lung cancer (NSCLC) xenograft models [200,209,214,215]. Tumor growth was reduced at plasma drug concentrations comparable to those seen in patients taking a dose of 400 mg daily [216]. Another study showed that MDA-MB–231 cells were sensitive to sorafenib treatment, with a 42% reduction in tumor mean size after only 9 days of treatment [200]. Mean micro vessel area and density were significantly reduced in sorafenib-treated tumors, indicating considerable angiogenesis inhibition in this tumor model consistent with its known inhibition of VEGFR [200]. A similar result was reported by Zanotto-Filho et al., where sorafenib, both alone and in combination with alkylating therapy, diminished tumor volume and vessel density of MDA-MB–231 mouse xenografts [211]. This study also determined that sorafenib treatment inhibited metastasis of orthotopic 4T1 tumors [211]. Moreover, sorafenib demonstrated moderate synergistic effects when combined with paclitaxel in a murine model of breast cancer bone metastasis (MDA-MB–231) [217]. Treated mice had significant reduction of both osteolytic lesions and soft tissue tumors [217]. Sorafenib also showed synergistic effects with the aromatase inhibitor letrozole, inhibiting proliferation and enhancing cell cycle arrest in aromatase-expressing MCF–7 cells [218].
3.4.4.2. Clinical findings.
Early Phase II trials of sorafenib as a monotherapy for the treatment of MBC patients with any prior chemotherapy (NCT00101400) or anthracyclines/taxanes specifically (NCT00096434) showed no significant clinical response [219,220]. Based on preclinical findings demonstrating inhibition of angiogenesis following sorafenib treatment [200,211], it was hypothesized that sorafenib could be beneficial for bevacizumab-resistant cancers by targeting alternative pro-angiogenic signals. Clinicians tested this concept by using sorafenib with chemotherapy for HER2-negative locally recurrent or metastatic patients who had failed bevacizumab therapy (NCT00493636). The trial determined that sorafenib with gemcitabine/capecitabine resulted in a significantly extended PFS [221], in contrast to sorafenib’s failure as a standalone therapy [219,220]. Interestingly, this may indicate that broader inhibition of VEGFR and PDGFR signaling can partially overcome resistance to VEGF-directed therapy. As such, sorafenib may be most effective when combined with other active chemotherapy.
In support of this, sorafenib has shown clinical efficacy in patients with HER2-negative advanced or metastatic breast cancer when combined with capecitabine. In a Phase II randomized clinical trial of 229 patients with the combination of sorafenib with capecitabine, treatment groups had a significant improvement of PFS compared to the placebo group (6.4 vs. 4.1 months) [222]. Similarly, sorafenib in combination with paclitaxel in HER2-negative MBC showed remarkable enhancement in PFS and overall response rate (ORR) [223]. Collectively, these studies suggested that sorafenib could enhance chemotherapy efficacy, potentially through non-tumor cell autonomous effects on both tumor angiogenesis and PDGFR-dependent stromal support.
Preclinical findings also indicated a potential synergistic effect between sorafenib and endocrine therapy [218]. To this end, a Phase II trial evaluated the efficacy of sorafenib in combination with letrozole in patients with HER2-negative MBC. Unfortunately, treatment did not provide any significant improvement, and a high number of treatments were discontinued due to adverse effects [224]. A second Phase II trial tested a combination of sorafenib and anastrozole in postmenopausal women with HR+ MBC (NCT00217399). While the combination provided a 23% clinical benefit rate, 31% of patients were removed from the study due to toxicity [225]. Similar results were observed in a study of ER+ breast cancer (NCT00525161) [226]. Moderate benefit to time to progression was seen in patients who received sorafenib in combination with tamoxifen, however all patients experienced toxicity from sorafenib treatment [226]. Grade III toxicities were also observed in studies of early-stage breast cancer, with little to no clinical benefit [227–229]. Additionally, in a Phase III double-blind trial comparing sorafenib with capecitabine versus capecitabine alone in HER2-negative breast cancer, the addition of sorafenib did not improve any survival metric and increased frequency of grade III toxicities (NCT01234337) [230].
The discrepancy between Phase II and Phase III outcomes likely reflects several factors, including breast cancer heterogeneity, activation of compensatory angiogenic and stromal signaling pathways, and the absence of biomarkers capable of identifying tumors dependent on PDGFR. Consequently, although sorafenib demonstrated biological activity and occasional improvements in progression-based endpoints, these benefits rarely translated into durable survival advantages. Overall, the clinical experience with sorafenib suggests that broad inhibition of VEGFR and PDGFR signaling is insufficient for unselected breast cancer populations. Future studies require biomarker-driven patient selection to identify tumors that are particularly dependent on PDGFR-associated stromal support or angiogenic signaling, while also developing strategies to mitigate the substantial toxicities associated with multikinase inhibition.
3.4.5. Nilotinib
Nilotinib (4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]benzamide) is a second-generation oral TKI originally designed to treat patients with imatinib-resistant BCR-ABL mutants and has shown superiority over imatinib in first-line treatment for CML [231]. Nilotinib has a higher potency than imatinib against Bcr-Abl kinases and an inhibitory rank order of Bcr-Abl>PDGFR>c-Kit. This is promising as a treatment for patients who have resistance to other TKIs, but it is not indicative of its higher ability to target PDGFR, as imatinib still has higher affinity at targeting PDGFR (rank order of potency: PDGFR>c-Kit>Bcr-Abl) [232]. Nonetheless, nilotinib is still a viable inhibitor of PDGFR (Fig. 1), with a mean IC50 value between 57 and 71 nM in cells whose proliferation is dependent on activated forms of PDGFR [233].
3.4.5.1. Preclinical findings.
Several preclinical studies have demonstrated nilotinib’s efficacy as a potential therapeutic for TNBC. Early in silico work utilized machine learning approaches to identify nilotinib as an effective TNBC therapy [234].Treatment with nilotinib in vitro has been shown to significantly inhibit invasion and migration and increase the rate of apoptosis in TNBC cell lines (MDA-MB–231, MDA-MB–468, MCF–7) [235–237]. A 2014 study by Blanchard et al. investigated the role of nuclear c-Abl and geminin expression in TNBC and demonstrated that inhibition of c-Abl by nilotinib led to regression of geminin-overexpressing orthotopic tumors [238].
Additionally, nilotinib has displayed potential as a treatment for metastatic breast cancers. Treatment of MDA-MB–231 cells with nilotinib in vitro decreases the formation of invadopodium precursors, a key step in the metastatic cascade [239]. Similarly, Wyss et al. demonstrated that nilotinib significantly inhibited the proliferation of metastatic breast cancer cells exhibiting propensity to metastasize to the brain (4T1-BM, D2A1-BM, MDA231-BrM) in vitro [41]. Interestingly, in both studies, nilotinib treatment did not affect primary mammary tumors but diminished the formation of lung and brain metastases, respectively, which suggest potential efficacy in the stage IV setting [41,239].
Mechanistically, studies have shown a connection between nilotinib and estrogen signaling. Weigel et al. determined that the PDGFR/Abl pathway is strongly associated with estrogen deprivation. Due to this correlation, nilotinib had increased efficacy against MCF–7 breast cancer cells with long-term estrogen deprivation and was able to suppress the expression of ER [240]. A second study illustrated that nilotinib inhibited the growth of tamoxifen-resistant MCF–7 breast cancers by reducing the expression and phosphorylation of ERα [241]. Nilotinib was also able to resensitize these cell lines to tamoxifen treatment. Further, combination treatment of nilotinib and rosuvastatin diminished in in vivo solid Ehrlich carcinoma tumor growth and ERα protein expression [242].
Preclinical studies have also revealed several potential drawbacks of nilotinib treatment that are a result of its multi-kinase affinity. Zafarnia et al. determined that nilotinib treatment enhanced angiogenesis of MCF–7 tumors, specifically through an increase in levels of VEGF and VEGFR2. Combination treatment of nilotinib with VEGFR2 neutralizing antibody (DC101) counteracted the reduction in vessel density seen by DC101 treatment alone [243]. Additionally, combination treatment of paclitaxel and nilotinib showed supralinear toxicity in a murine xenograft model [244].
3.4.5.2. Clinical findings.
There are currently two active Phase II clinical studies investigating nilotinib intervention in breast cancer (NCT05185947, NCT05564377), however results of these studies have not yet been reported [245]. That said, nilotinib has been tested clinically in CML, GIST, and advanced solid tumors, and as mentioned above, nilotinib is approved as a first-line treatment for CML. Long-term follow-up studies further demonstrated durable major molecular response (MMR) and progression-free survival benefits compared with imatinib in CML and GIST [246–248]. These findings established nilotinib as an effective targeted therapy in cancers driven by kinase-dependent oncogenic signaling. Nilotinib has also been well tolerated in dose escalation Phase I studies and Phase II studies of GISTs, which are most often driven by PDGFR signaling [249,250]. Additionally, nilotinib has shown clinical benefit as a monotherapy in patients who do not respond to other TKIs, such as imatinib and sunitinib, suggesting that nilotinib may retain efficacy in tumors with acquired resistance to earlier-generation kinase inhibitors [249–252]. Recently, nilotinib has shown tolerability in the treatment of solid tumors with sustained stable disease or partial response [253–255].
Despite these encouraging findings, the applicability of nilotinib to breast cancer remains unclear. Unlike CML, which is driven by oncogenic kinase activity, most breast cancers exhibit substantial heterogeneity and are rarely dependent on a single signaling pathway. Therefore, the success of nilotinib in breast cancer may depend on identifying patient subgroups with increased PDGFR-mediated stromal interactions and consideration of how stromal heterogeneity changes as the disease progresses in the metastatic setting. Given its favorable clinical experience in CML, GIST, and other solid tumors, investigation of nilotinib as a neoadjuvant or adjuvant strategy in biomarker-selected breast cancer patients appears warranted.
3.4.6. Crenolanib
Crenolanib (1-(2-{5-[(3-methyloxetan-3-yl)methoxy]-1H-benzimi dazol-1-yl}quinolin-8-yl)piperidin-4-amine; formerly CP-868,596, PubChem CID: 10366136) is an oral TKI of PDGFR. Unlike other antiangiogenic TKIs, crenolanib is greater than 100-fold more selective for inhibiting PDGFR than other tyrosine kinases, such as VEGFR, and c-Kit (Fig. 1) [256]. The dosing for crenolanib is also considerably low, with an IC50 of 1 ng/mL and 0.4 ng/mL for PDGFRα and PDGFRβ, respectively [256]. Although crenolanib is not yet approved for cancer treatment, it has been tested in clinical trials of GISTs (NCT01243346, NCT02847429), AML [257], glioma [258], and esophagogastric adenocarcinoma [259].
3.4.6.1. Preclinical findings.
Due to the high frequency of PDGFRα mutations in GIST, crenolanib was first tested in these models by Heinrich et al. in 2012. This study determined that crenolanib is significantly more potent against mutant PDGFRα than imatinib [260]. Additionally, crenolanib inhibits the growth of imatinib-resistant GIST cells and in vivo GIST xenografts [261]. Similarly, preclinical studies of AML demonstrate that crenolanib is an inhibitor of FLT3 and is effective against drug-resistant FLT3-ITD mutant AMLs both in vitro and in vivo [262]. Crenolanib has also been shown to suppress the proliferation and tumor growth of NSCLC [263].
Regarding breast cancer models, crenolanib effectively inhibits cell growth and induces apoptosis in models of inflammatory breast cancer (IBC) (SUM149 and KPL–4) [104]. This study also exhibited crenolanib’s ability to block in vivo tumor growth of the IBC cell line SUM149 [104]. We have previously published an in vivo study that demonstrates crenolanib’s efficacy at reducing the growth of intracranial mammary tumor cells that express high levels of PDGFB [42]. Mechanistically, a study by Imamura et al. reported that crenolanib treatment alters crosstalk between breast cancer cells (4T1) and fibroblasts (NIH/3T3) [264]. Specifically, the team used a system where 4T1 conditioned media induced fibroblast production of the chemokine MCP–1, and in this system, crenolanib-treated fibroblasts had significantly reduced MCP–1 production [264].
3.4.6.2. Clinical findings.
Clinical trials have shown tolerability at the Phase I level when compared to other oral TKIs [256,258,259]. A recent clinical trial of FLT3-mutated AML demonstrated long-term tolerability of crenolanib. Patients had an overall response rate of 86%, with younger patients (<60) having a slight benefit compared to patients > 60 [265]. Phase II/III clinical trials are currently ongoing for GIST (NCT02847429) and AML (NCT03620318, NCT03258931, NCT03250338), but no trials in breast cancer have been initiated. Based on promising preclinical data, further clinical data on the efficacy of crenolanib is warranted, particularly in biomarker selected patients with high tumor epithelial PDGFB and/or evidence of PDGFR activation in the TME.
3.4.7. CP-673,451
Another TKI that has proven effective at inhibiting PDGFRα/β is CP–673,451 (1-[2-[5-(2-methoxyethoxy)benzimidazol-1-yl]quinolin-8-yl]piperidin-4-amine; PubChem CID: 10158940). With a low IC50 value of 1 nM, it is extremely selective for PDGFR, > 450 fold over VEGFR, TEK receptor tyrosine kinase (TIE2), and fibroblast growth factor receptor–2 (FGFR2) (Fig. 1). In early proof of concept studies, CP–673,451 was shown to inhibit a remarkable 70% of PDGF-BB induced angiogenesis in an in vivo sponge angiogenesis model [266], yet whether this functional consequence will translate to better patient outcomes remained to be determined.
3.4.7.1. Preclinical findings.
Early studies have shown that CP-673,451 can reduce xenograft tumor volume in models of colon cancer, lung cancer, and rhabdomyosarcoma [267–269]. Regarding its use in breast cancer studies, CP-673,451 was found to be independently effective at inhibiting metastasis of breast cancer to the lungs in mice, though it did not affect the primary tumor growth in this experiment until it was combined with the serum/glucocorticoid regulated kinase 1 (SGK1) inhibitor, GSK-650,394 [270]. To our knowledge, clinical work has not yet been initiated for CP-673,451. However, considering the high potency and low concentrations required to target PDGFR using CP-673, 451, continuing research into its effectiveness as a targeted drug is necessary.
3.4.8. Future success of small molecule inhibitors
Despite strong preclinical evidence supporting PDGF-PDGFR-targeting as a method of treatment in breast cancer patients, clinical translation has been largely unsuccessful. Several factors likely contribute to this disconnect. First, many of the inhibitors lack specificity and simultaneously target multiple kinases, leading to off-target effects and toxicity. Second, tumor heterogeneity across breast cancer subtypes may dilute therapeutic efficacy in unselected patient populations. Third, PDGF-PDGFR signaling plays a prominent role in the TME, suggesting that targeting this axis as a monotherapy may be insufficient without concurrent modulation of stromal or immune components. These limitations highlight the need for improved patient selection, specifically by stratifying patients based on PDGF/PDGFR expression, and the use of combination therapies to fully realize the therapeutic potential of PDGF inhibition in breast cancer.
We must further consider that the most impactful clinical utility may be in the metastatic setting or in high risk cases. Multiple preclinical studies suggest PDGF-PDGFR signaling regulates processes involved in metastatic progression. This includes vascular changes and immune modulation. This is especially evident in models of breast cancer associated brain metastases as discussed above. Thus, renewed evaluation of PDGF-PDGFR inhibitors may be most appropriate in biomarker-selected populations with established metastatic disease or in patients at high risk for brain metastasis-specific recurrence. In the latter case, primary tumor PDGFB expression may serve as a candidate biomarker to identify those individuals at who should be monitored closely for CNS spread and/or prevention strategies.
3.5. Combination treatment strategies to target PDGF-PDGFR signaling
An emerging strategy to overcome limited efficacy and toxicity of PDGF-PDGFR-targeted monotherapies is the use of rational combination therapies. Given the pathway’s central role in tumor-stromal interactions and TME regulation, combining PDGF-PDGFR inhibition with other therapeutic strategies may yield improved clinical outcomes.
3.5.1. PDGF inhibition and chemotherapy
Multiple preclinical and clinical studies suggest PDGF-PDGFR inhibition may be most effective when combined with chemotherapy rather than administered as monotherapy. Evidence supporting this concept has been observed with several PDGFR inhibitors. Imatinib enhanced vinorelbine-induced apoptosis in breast cancer lines [146]. Sunitinib demonstrated additive or synergistic activity when combined with docetaxel, doxorubicin, 5-fluorouracil, and trastuzumab in preclinical models [183,185]. Similarly, pazopanib exhibited increased anti-tumor activity and apoptosis when combined with topotecan in a xenograft model [168]. Sorafenib also demonstrated moderate synergistic effects when combined with paclitaxel [217].
Clinical studies largely mirror these findings. Although monotherapy with these TKIs generally failed to produce durable responses, several combination trials reported improvements in PFS or clinical benefit rates, with pazopanib and sorafenib being the most effective. Pazopanib in combination with chemotherapy has shown partial response or clinical benefit in MBC patients in multiple clinical trials (NCT00388076, NCT00347919, NCT01498458) [171–173]. Sorafenib has been successful in combination with chemotherapy in two settings. Sorafenib with gemcitabine/capecitabine resulted in a significant increase in PFS for patients who had failed bevacizumab therapy (NCT00493636) [221]. Sorafenib also demonstrated improved PFS when combined with chemotherapy in HER2-negative MBC [222,223]. Unfortunately, imatinib and sunitinib have not demonstrated significant clinical benefit when combined with chemotherapy.
These studies suggest that pazopanib and sorafenib may function best as chemo-sensitizing agents rather than monotherapies. Future studies should evaluate whether patients with elevated PDGF/PDGFR expression derive greater benefit from chemotherapy combination treatments.
3.5.2. PDGF inhibition and endocrine therapy
Several lines of evidence support functional interactions between PDGF-PDGFR signaling and ER signaling. PDGF pathway activation has been associated with endocrine resistance, and expression of PDGFRβ was reported to increase following aromatase inhibitor treatment in ER+ breast cancer [106]. Multiple studies using nilotinib demonstrated suppression of ERα expression and restoration of sensitivity to endocrine therapy in tamoxifen-resistant models [240,241]. Moreover, evidence implicates PDGFC in ER+ metastatic dormancy and outgrowth in the lung, raising the possibility that PDGF-PDGFR could be combined with endocrine therapy to prevent metastatic recurrence in patients with ER+ disease [68].
Clinical translation of this concept has produced mixed results. A trial evaluating imatinib plus letrozole was well-tolerated, but showed limited response in HR+ MBC (NCT00338728) [161]. Sorafenib has been tested in combination with endocrine therapy in several Phase II trials (NCT00217399, NCT00525161). While these studies demonstrated moderate clinical benefit, a large portion of patients were removed from study due to toxicities [224–226]. Nevertheless, the underlying biological rationale remains compelling. Selective PDGFR inhibitors, such as crenolanib, may prove more effective by minimizing off-target effects while preserving anti-cancer inhibition of PDGF-PDGFR pathways.
3.5.3. PDGF inhibition and immunotherapy
The immunomodulatory functions of PDGF-PDGFR signaling provide a strong rationale for combining pathway inhibition with immunotherapy. PDGF signaling contributes to multiple features of an immune-excluded TME, including fibroblast activation, extracellular matrix deposition, vascular abnormalities, and recruitment or maintenance of immunosuppressive cell populations [42,62,67]. PDGFC has been implicated in the survival of tumor-associated macrophages through PDGFRα signaling [63], while stromal PDGFR signaling drives CAF activation and fibrosis [67,83]. Together, these processes may impair immune-cell infiltration and limit effective anti-tumor immune responses.
Preclinical evidence supporting PDGF-directed immunomodulation is already emerging. The anti-PDGFRβ aptamer Gint4.T enhanced the efficacy of anti-PD-L1 therapy in the 4T1 TNBC model, reducing both primary tumor growth and lung metastasis while increasing T-cell infiltration [140]. More recently, a PDGFRβ-targeted CD40 agonist strategy was developed to selectively activate anti-tumor immunity within PDGFRβ-positive stromal regions [132]. Collectively, these findings suggest that targeting PDGF signaling may improve immunotherapy responsiveness through both stromal and vascular remodeling.
Importantly, TNBC may represent the most suitable clinical context for these combination approaches. TNBC frequently exhibits elevated PDGF/PDGFR expression, extensive CAF infiltration, and greater dependence on EMT- and CSC-associated mechanisms linked to PDGFR signaling [48,60,72,85]. Because immune checkpoint inhibitors are already incorporated into the treatment paradigm for subsets of TNBC patients, combining PDGF pathway inhibition with immunotherapy represents a logical future direction. Biomarker-guided clinical trials incorporating stromal PDGFRβ expression, PDGF ligand abundance, or PDGF signaling signatures may help identify patient populations most likely to benefit from these approaches.
4. Conclusions and Future Directions
The PDGF-PDGFR signaling axis is a critical driver of breast cancer progression and metastasis. As detailed throughout this review, the expression of PDGF ligands (PDGFA, PDGFB, PDGFC, PDGFD) and their receptors (PDGFRα, PDGFRβ) are aberrantly elevated in a subset of breast cancers. Additionally, each is functionally diverse, contributing to pro-tumorigenic autocrine and paracrine signaling. These roles include EMT, CSC maintenance, desmoplasia, angiogenesis, and immune modulation, each of which plays a role in primary tumor growth, metastatic spread and modulating breast cancer patient outcomes.
Importantly, the spatial and temporal expression of PDGF ligands and receptors varies across breast cancer subtypes and metastatic sites. For example, PDGFA and PDGFB have been implicated in brain metastasis, particularly in HER2+ and TNBC, while PDGFC is often enriched in basal-like subtypes and associated with fibroblast activation and metastatic dormancy. PDGFD has shown potential roles in EMT and lymph node metastasis, although further studies are required. While PDGFC is lowly expressed in luminal breast cancers, several studies have identified ER-specific mechanisms. Expression of both PDGFRs has been linked to TNBC, and PDGFRβ specifically plays a prominent role in TNBC growth and metastasis. These findings underscore the need to consider patient-specific variables, including subtype, stage of disease, and metastatic sites, when considering therapeutic strategies.
The prognostic utility of PDGF-PDGFR signaling is well supported by clinical dataset analysis from our group and others (Table 2). High expression of PDGFA, PDGFB, PDGFC, and PDGFRβ correlate with reduced OS, MFS, and DFS. High expression of PDGFA and PDGFB mRNA are both predictive of shorter BrMFs, the metastatic site with the worst survival outcomes. Stromal PDGFRβ expression has also been shown to be reliable marker of poor prognosis and drug response, including diminished response to both radiotherapy and aromatase inhibitors. Based on these datasets, elevated expression of PDGFA, PDGFB, PDGFC, and PDGFRβ protein are most reliably associated with worse prognosis and could serve as valuable biomarkers for patient stratification and treatment planning. Specifically, primary tumor PDGFB could be particularly useful to identify patients at high risk for brain metastasis-specific recurrence, although prospective validation is required.
As shown in Fig. 1, there are currently several options available to target PDGF-PDGFR signaling. While no PDGF-PDGFR-targeted agents are currently approved for breast cancer, multiple targeting strategies have shown success in preclinical work. Neutralizing antibodies against PDGF ligands and receptors have been shown to reduce tumor growth, metastasis, and stromal PDGFR activation. Aptamers, such as Gint4.T targeting PDGFRβ, have effectively inhibited TNBC progression and enhanced immune infiltration. Multi-TKIs, including imatinib, pazopanib, sunitinib, sorafenib, and nilotinib, have yielded mixed results, with some showing benefit in combination regimens or specific subtypes, but have had limited success as monotherapies in clinical trials. Past and currently active clinical trials associated with the discussed small molecule inhibitors are listed in Table 3. Importantly, the failure of imatinib, sunitinib, and sorafenib in treating metastatic breast cancer highlights the importance of selective targeting to increase efficacy and safety. It is likely that only specific subsets of breast cancer patients will benefit from specific small molecule inhibitors, highlighting the need to consider PDGF ligand and receptor expression when considering the potential utility of these therapies.
Moving forward, the clinical translation of PDGF-PDGFR-targeted therapies will require a better understanding of patient specific ligand and receptor expression and subtype-specific treatment efficacy. Specifically, researchers should focus on completing confirmatory multi-variate analysis of stromal PDGFRβ and PDGF-PDGFR signatures as prognostic tools. Identifying patients who may benefit from PDGF-PDGFR inhibition will allow for a more precise and effective treatment strategy, specifically those with elevated expression of PDGF ligands and receptors. Additionally, based on what is known to date, TNBC patients may benefit the most from PDGF-PDGFR inhibition. Combination PDGF-PDGFR inhibition and immunotherapy could also be a viable strategy, particularly in patients with high levels of stromal PDGFRα/β. The continued development of highly selective small molecule inhibitors, such as crenolanib and CP-673,451, will allow for more precise targeting, which could greatly reduce side effects seen with other multi-tyrosine kinase inhibitors and therefore increase efficacy and safety. Research groups should consider prioritizing the discovery of selective tyrosine kinase inhibitors for PDGFR to avoid the failures seen with multi-tyrosine kinase inhibitors.
In summary, PDGF-PDGFR signaling is a complex and clinically relevant pathway in breast cancer. The pathway’s roles in tumor growth, metastasis, prognostic stratification, and therapeutic resistance highlight its usefulness as a therapy target that should be considered for future research and drug development. Continued investigation into its pro-tumorigenic mechanisms and translational potential is essential for advancing breast cancer treatment and improving patient outcomes.
Acknowledgments
Work conducted in the Sizemore laboratory on PDGF signaling in breast cancer has been supported by the Department of Defense Breast Cancer Research Program (W81XWH–21–1–0021 to G.M.S.) and the National Institutes of Health (K22CA218472 and R37CA282660 to G.M.S).
Footnotes
Declaration of generative AI and AI-assisted technologies in the manuscript preparation process
During the preparation of this work, the authors used Microsoft Copilot to improve readability, grammar, and to assist in drafting revisions based on published literature. After using this tool, the authors reviewed, edited, and verified all content and take full responsibility for the content of this publication.
CRediT authorship contribution statement
Jesse J. Reardon: Writing – review & editing, Writing – original draft, Visualization, Investigation, Conceptualization. Alexis A. Mossing: Writing – review & editing, Writing – original draft, Visualization, Investigation, Conceptualization. Rebecca L. Packard: Writing – review & editing, Writing – original draft, Visualization, Investigation, Conceptualization. Sajita Shah: Writing – review & editing, Writing – original draft, Visualization, Investigation, Conceptualization. Gina M. Sizemore: Writing – review & editing, Writing – original draft, Supervision, Conceptualization, Resources.
Declaration of Competing Interest
All authors have nothing to declare.
Data availability
No data was used for the research described in the article.
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